Pyridine → HCID 11351286, compound

HRID 2377028Notes

Reaction equation

HRID 2377028 reaction equation
N1C=CC=CC=1.C(OC(=O)C)(=O)C.[C:14]([N:17]1[CH2:21][C@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:19]([O:28][C@H:29]([C:31]2[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([C:41]([F:44])([F:43])[F:42])[CH:32]=2)[CH3:30])[CH2:18]1)(=[O:16])[CH3:15]>C(Cl)Cl>[C:14]([N:17]1[CH2:21][C@H:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@@H:19]([O:28][C@@H:29]([C:31]2[CH:32]=[C:33]([C:41]([F:42])([F:43])[F:44])[CH:34]=[C:35]([C:37]([F:39])([F:38])[F:40])[CH:36]=2)[CH3:30])[CH2:18]1)(=[O:16])[CH3:15]

Participants

5

Reactant 3

HCID 1049PyridineHCID 7918Acetic AnhydrideHCID 86610905HCID 86610905, compound

Product 1

HCID 11351286HCID 11351286, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 200 mg intermediate step E (0.47 mmol) in 3 mL dry methylene chloride at 0° C. was added 0.097 mL pyridine (1.18 mmol) followed by 0.089 mL acetic anhydride (0.94 mmol). The reaction mixture was stirred for 6 hr at ambient temperature then the volatiles were removed under vacuum. The residue was partitioned between 2N aq. NaOH (5 mL) and methylene chloride (10 mL). The layers were separated and the aqueous layer extracted with methylene chloride (2×5 mL). The combined organic extracts were dried over sodium sulfate, filtered and solvent evaporated under vacuum. The resulting material was purified by preparative TLC eluting with methylene chloride/methanol (9/1). The resulting material was further purified by prep HPLC on Chiralpak AD column eluting with heptanes/ethanol (97/3) to afford a minor faster moving isomer A (3R,4S)-1-acetyl-3-({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-phenylpyrrolidine and the title compound. 1H-NMR (CDCl3) rotamers: δ: 1.45 (t, 3H, 6.5 Hz), 2.15 (2s, 3H) 3.38-3.63 (m, 3H), 3.85-4.03 (m, 3H), 4.58 (m, 1H), 7.1 (m, 2H), 7.25 (m, 3H), 7.61 (s, 2H), 7.78 (s, 1H)ppm. MS: 446 (MH)+ observed.

Workup

  1. customthe volatiles were removed under vacuum
  2. customThe residue was partitioned between 2N aq. NaOH (5 mL) and methylene chloride (10 mL)
  3. customThe layers were separated
  4. extractionthe aqueous layer extracted with methylene chloride (2×5 mL)
  5. dry with materialThe combined organic extracts were dried over sodium sulfate
  6. filtrationfiltered
  7. customsolvent evaporated under vacuum
  8. customThe resulting material was purified by preparative TLC
  9. washeluting with methylene chloride/methanol (9/1)
  10. customThe resulting material was further purified by prep HPLC on Chiralpak AD column
  11. washeluting with heptanes/ethanol (97/3)
  12. customto afford a minor

Sources & evidence

ORD record
ord-b8db151ae63e467a922436ce8e7029c2
Source dataset
uspto-grants-2008_12
Patent number
US07468437B2

Reaction notes

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